Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. This study focuses on the mechanisms by which liver growth and function is regulated by receptor guanylyl cyclases, molecules that link extracellular signals to the generation of cyclic GMP (cGMP), a critical intracellular signaling molecule. Among other known actions, cGMP is strongly linked to mechanisms regulating programmed cell death, or apoptosis. Within hours of liver damage or cellular loss, there is a dramatic upregulation of guanylyl cyclase C, a cGMP-forming receptor guanylyl cyclase. GC-C is activated by the proteins guanylin and uroguanylin. During regeneration, the liver is exposed to a number of hormones and growth factors, most notably TNF-alpha, which are known inducers of apoptosis. The central hypothesis of this proposal is that ligand-mediated activation of the receptor guanylyl cyclases protects regenerating hepatocytes and non-parenchymal cells from the lethal actions of the various cytokines involved in the regenerative response. The guanylyl cyclases may also be critical to restraining hepatocyte proliferation to achieve normal liver mass and to prevent neoplasia. We aim to determine: 1) how liver regeneration in response to three different stimuli is altered in GC-A or GC-C gene-targeted mice; 2) the consequences of particulate guanylyl cyclase activation on apoptosis and cell proliferation; and 3) how membrane guanylyl cyclases alter apoptotic signaling mechanisms in cultured hepatocytes and in regenerating liver. Progress toward these aims will improve our understanding of how the liver inhibits programmed cell death during the dramatic restoration of liver growth of regeneration. Liver regeneration is a paradigm for other conditions of normal and altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating mechanisms of growth control in the liver, our studies may ultimately aid in developing methods to reduce liver cell death following viral or toxic injury during transplantation and in the differentiation of precursor cells for transplantation and bio-artificial livers.